Debromohymenialdisine (DBH) 2 is a C.sub.11 N.sub.5 marine sponge alkaloid that was first isolated from an Okinawan sponge, Hymeniacidon sp. ##STR2##
Horne et al., "Synthesis of C.sub.11 N.sub.5 Marine Sponge Alkaloids: (.+-.)-Hymenin, Stevensine, Hymenialdisine, and Debromohymenialdisine," J. Org. Chem., 62:456-464, 456 (1997).
Known analogs of DBH include hymenin 4, stevensine 6, and hymenialdisine 8. ##STR3##
These natural products are the primary family members of the sponge metabolites that contain a fused pyrrolo[2,3-c]azepin-8-one ring system having either a 2-aminoimidazole or glycocyamidine appendage. Id.
Hymenin 4 has been shown to have potent .alpha.-adrenoreceptor-blocking properties. Kobayashi, J. et al., Experientia 42; 1064 (1986); Kobayashi, J. et al. The Alkaloids: Chemistry and Pharmacology, 41: 41-124 (1992); and Faulkner, D. J., J. Nat. Prod. Rep., 13: 75 (1996). Moreover, DBH 2 can be used to treat subjects having osteooarthritis, which is a progressive, irreversible disease characterized by pain and loss of function caused by cartilage degradation. Chipman et al., U.S. Pat. No. 5,591,740 (the '740 patent), column 1, lines 7-18. Osteoarthritis can result in the complete erosion of weight-bearing articular cartilage, which may require total joint replacement. Id. Pro-inflammatory cytokine interluekin-1 (IL1) apparently plays a role in the cartilage matrix destructive processes observed in osteoarthritis. Pelletier et al., Sem. Arth. Rheum., 20:12 (1991); and McDonnell, et al., Arth. Rheum., 35:799 (1992).
Prior to the Chipman et al. invention described in the '740 patent, there were few, if any, therapeutic approaches that effectively slowed the clinical progression of osteoarthritis. The '740 patent, supra. The method for treating subjects having osteoarthritis described in the '740 patent comprises administering to individuals therapeutically effective amounts of DBH.
A commercially viable and efficient method for making DBH, and biologically active analogs thereof, is required to treat the number of patients having osteoarthritis, and other afflictions, who potentially might benefit from such treatments. Some methods are known for making hymenialdisine and DBH. See, for example, Horne et al., J. Org. Chem. 51:456-464 (1997), supra; Horne et al., U.S. Pat. No. 5,834,609, incorporated herein by reference; Horne et al., U.S. patent application Ser. No. 09/016,748, which is incorporated herein by reference; and Annoura et al., U.S. Pat. No. 5,621,099. These prior syntheses do not provide commercially viable methods for making DBH for several reasons, including (1) the yield of DBH is too low in the final step or steps of the synthesis, (2) the prior methods require too many synthetic steps overall, and (3) purification of the products. Therefore, despite these previous approaches, a more efficient and economically viable method for synthesizing bicyclic aminoimidazoles, such as DBH and analogs thereof, is needed.